Gender-Dependent Effects of Stress During Adolescence on Adult Brain and Behavior

青春期压力对成人大脑和行为的性别依赖性影响

• 批准号: 8334736
• 负责人: KALYNN SCHULZ
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334736
• 关键词: Accounting; Adolescence; Adolescent; Adolescent Development; Adult; Afghanistan; Age; Age-Years; Animals; Anxiety; Attentional deficit; Automobile Driving; Behavior; Behavioral; Brain; Brain region; Cells; Clinical; Depressed mood; Depressive disorder; Development; Disease; Environment; Environmental Risk Factor; Exposure to; Functional disorder; Future; Gender; General Population; Goals; Health; Hippocampus (Brain); Hormones; Human; Hydrocortisone; Individual; Individual Differences; Intervention; Iraq; Knowledge; Life; Link; Major Depressive Disorder; Mediating; Memory; Mental Depression; Mental disorders; Military Personnel; Modeling; Nervous system structure; Neurobiology; Nicotine; Nicotinic Receptors; Outcome; Performance; Perinatal Exposure; Phase; Post-Traumatic Stress Disorders; Pre-Clinical Model; Preventive Intervention; Psychopathology; Psychotic Disorders; Quality of life; Recording of previous events; Regulation; Risk; Rodent Model; Schizophrenia; Services; Shapes; Smoke; Smoking; Soldier; Stress; Symptoms; Testing; Time; Veterans; War; Work; behavior test; behavioral impairment; brain behavior; cognitive function; combat; depressive symptoms; disability; experience; high risk; improved; lifetime risk; nerve injury; neuromechanism; nicotinic receptor beta2; postnatal; pre-clinical; prenatal; prenatal stress; prevent; programs; receptor; relating to nervous system; research study; resilience; sex; stress related disorder; stressor; young adult

DESCRIPTION (provided by applicant): Stress exposure during development is associated with mental illnesses that afflict veterans. Schizophrenia currently accounts for a staggering 19% of all veteran full disability cases, and depression and anxiety-related disorders such as post-traumatic stress disorder are common in veterans returning from service. Depressive disorders and schizophrenia have etiological links to both prenatal and adolescent periods of development. Importantly, adolescent brain development in humans extends into the early twenties (even 24 for some brain regions), which overlaps significantly with the time-frame for military service. Thus, increased scientific understanding of how stress during development impacts brain development and stress-related disorders is imperative to the health of our veterans. Despite recent clinical advances in identifying adolescents at high risk for psychosis, the ability of available models to accurately predict psychotic conversion is less than 30%, suggesting that unidentified factors are contributing significantly to an individual's risk for psychosis. One possible factor is the developmental stress history of an individual. While studies often account for adolescent stress exposure and/or cortisol levels when assigning a "high risk" designation, current models have not included stress experienced by individuals at earlier developmental time points. From the standpoint of sensitive periods of brain development, and individual's previous stressful experiences may alter the course of brain development in a manner that confers increased risk, or even resilience, to the impact of subsequent stressors. Despite the known relationships between stress exposure during prenatal and adolescent development and mental illness, whether prenatal stress exposure increases sensitivity to stress during adolescence is not known. Preclinical rodent models have enormous potential for elucidating the relationships between the timing of stress exposure across development and brain dysfunction. Therefore, Aim 1 will test the hypothesis that prenatal stress exposure programs the impact of adolescent stress on subsequent behavioral function in a sex-specific manner. This hypothesis predicts that (1) the combined effects of prenatal and adolescent stress on adult behavioral function will differ from the isolated effects of stress during either time period alone, (2) identical stressors experienced in adulthood will not result in the same magnitude of behavioral impairments (3) the behavioral effects of developmental stress will depend on the sex of the animals. Aim 2 will investigate the neural mechanisms by which developmental stress exposure impacts adult behavioral function. Hippocampal nicotinic receptor abnormalities are present in psychiatric illnesses such as depression and schizophrenia, and are important regulators of memory function and anxiety-related behaviors. Therefore, Aim 2 will test the hypothesis that stress-dependent behavioral changes are mediated by alterations in nicotinic receptor levels and/or function. This hypothesis predicts that levels and/or function of nicotinic receptors will vary as consequence of stress experienced prenatally or during adolescence. Ultimately, this work will advance our knowledge of the developmental and environmental factors contributing to individual differences in vulnerability to psychopathology, and allow for better targeting of the timeframe for prevention and intervention in our veterans. PUBLIC HEALTH RELEVANCE: Many psychiatric illnesses afflicting veterans are associated with stress exposure during early development and late adolescence. Indeed, disorders such as depression and schizophrenia typically develop during adolescence, which spans the ages most common for military service (17-24). Thus, understanding how stress exposure alters brain development and risk for mental disorders such as schizophrenia and depression is imperative to the health of veterans, especially during war time. The current studies investigate in a preclinical model the effects of stress during development on behavioral function, and whether stress-induced behavioral deficits are caused by changes in brain nicotinic receptors. The results of these studies are important for developing gender-specific interventions aimed at preventing and improving the debilitating symptoms of mental illnesses experienced by veterans.

描述（由申请人提供）： 发育过程中的压力暴露与困扰退伍军人的精神疾病有关。目前，精神分裂症占所有退伍军人完全残疾病例的 19%，令人震惊，而抑郁症和焦虑相关疾病（如创伤后应激障碍）在退伍军人中很常见。抑郁症和精神分裂症与产前和青少年时期的发育都有病因学联系。重要的是，人类青少年时期的大脑发育持续到二十岁出头（某些大脑区域甚至是二十四岁），这与服兵役的时间框架有很大重叠。因此，加强对发育过程中的压力如何影响大脑发育和压力相关疾病的科学理解对于我们退伍军人的健康至关重要。尽管最近在识别精神病高风险青少年方面取得了临床进展，但现有模型准确预测精神病转变的能力还不到 30%，这表明未识别的因素对个体患精神病的风险有显着影响。一个可能的因素是个体的发育压力史。虽然研究在指定“高风险”时通常会考虑青少年的压力暴露和/或皮质醇水平，但当前的模型并未包括个人在早期发育时间点经历的压力。从大脑发育敏感期的角度来看，个人以前的压力经历可能会改变大脑发育的过程，从而增加对后续压力源影响的风险，甚至增强抵御能力。尽管已知产前和青少年发育期间的压力暴露与精神疾病之间的关系，但产前压力暴露是否会增加青春期期间对压力的敏感性尚不清楚。临床前啮齿动物模型在阐明发育过程中压力暴露时间与脑功能障碍之间的关系方面具有巨大潜力。因此，目标 1 将检验以下假设：产前压力暴露以特定性别的方式影响青少年压力对后续行为功能的影响。该假设预测（1）产前和青少年压力对成年行为功能的综合影响将有所不同 从单独任一时间段内压力的孤立影响来看，（2）成年期经历的相同压力源不会导致相同程度的行为障碍（3）发育压力的行为影响将取决于动物的性别。目标 2 将研究发育压力暴露影响成人行为功能的神经机制。海马烟碱受体异常存在于抑郁症和精神分裂症等精神疾病中，是记忆功能和焦虑相关行为的重要调节因子。因此，目标 2 将检验以下假设：压力依赖性行为变化是由烟碱受体水平和/或功能的改变介导的。该假设预测烟碱受体的水平和/或功能将由于产前或青春期经历的压力而变化。最终，这项工作将增进我们对导致心理病理学脆弱性个体差异的发育和环境因素的了解，并更好地确定退伍军人预防和干预的时间表。 公共卫生相关性： 许多困扰退伍军人的精神疾病都与早期发育和青春期后期的压力暴露有关。事实上，抑郁症和精神分裂症等疾病通常发生在青春期，这个年龄段是服兵役最常见的年龄段（17-24 岁）。因此，了解压力如何改变大脑发育以及精神分裂症和抑郁症等精神疾病的风险对于退伍军人的健康至关重要，尤其是在战争时期。目前的研究在临床前模型中调查了发育过程中的压力对行为功能的影响，以及压力引起的行为缺陷是否是由大脑烟碱受体的变化引起的。这些研究的结果对于制定针对性别的干预措施非常重要，这些干预措施旨在预防和改善退伍军人所经历的精神疾病的衰弱症状。